Tricyclic heterocyclic compounds, their production and use

ABSTRACT

Novel heterocyclic compound of the general formula: ##STR1## wherein ring A and ring B each means a benzene ring which is substituted or unsubstituted; X means a group of the formula: ##STR2## wherein R 2  is hydrogen an alkyl or an alkoxy; m is 0 or 1, the formula: ##STR3## wherein R 3  is hydrogen or an alkyl, or the formula: --O--CO--; Y means a bond, --NH--, an C 1  or 2 alkylene group or --CH═CH--; R 1  means a hydrocarbon group which is substituted or unsubstituted; and n means a whole number of 3 through 6, or a salt thereof, having excellent acyl-CoA:cholesterol acyltransferase inhibitory activity, and a method for preparing it and its use.

This application is a divisional of Ser. No. 07/765,182, filed Sep. 25,1991, now U.S. Pat. No. 5,264,454.

(a) Industrial Field of Utilization

The present invention relates to novel heterocyclic compounds havingexcellent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitoryactivity.

(b) Prior Art

Among quinoline, 2-quinolone and coumarin derivatives substituted bynitrogen in position-3 and phenyl in position-4, compounds whosepositions-6 and 7 are linked through --(CH₂)_(n))-- to form a ring havenot been known and, for that matter, never been a subject of researchfor possible exploitation as an agent for arteriosclerosis or a bloodcholesterol lowering agent.

(c) Problems that the Invention is to Solve

The present invention is primarily directed to the provision of a novelheterocyclic compound or salt which has excellent acyl-CoA:cholesterolacyltransferase inhibitory activity, suppresses absorption ofcholesterol from the intestinal tract and accumulation of cholesterol inthe arterial wall in mammalian animals and, as such, is of value as aprophylactic and therapeutic agent for hyper-cholesterolemia,atherosclerosis and various diseases associated therewith (for example,ischemic heart diseases such as myocardial infarction etc. andcerebrovascular disorders such as cerebral infarction, cerebralapoplexy, etc.). The invention is further directed to a commerciallyuseful process for producing said novel compound and a medicinallyuseful composition or pharmaceutical preparation containing said novelcompound.

(d) Means for Solving the Problems

The extensive research of the inventors of the present invention intoheterocyclic compounds revealed that a heterocyclic compound of thegeneral formula: ##STR4## wherein ring A and ring B each mean a benzenering which is substituted or unsubstituted, X means a group of theformula: ##STR5## (R² is hydrogen, alkyl or alkoxy; m is 0 or 1), theformula: (R³ is hydrogen or alkyl) or the formula: --O--CO--; Y means abond, --NH--, C₁ or 2 alkylene or --CH═CH--; R¹ means a hydrocarbongroup which is substituted or unsubstituted; and n means a whole numberof 3 through 6, or a salt thereof, which is characterized in that acycloalkyl group is condensed with ring B to form a chemically uniqueheterotricyclic system, has greater ACAT inhibitory activity thancompounds having an uncondensed heterocycle or those having ahetero-bicyclic system owing to the above unique chemical structure and,as such, is of value as a cholesterol lowering agent and/or atherapeutic drug for arteriosclerosis. The present invention ispredicated on the above findings.

The present invention, therefore, relates to:

(1) a heterocyclic compound of the formula (I) or a pharmaceuticallyacceptable salt thereof;

(2) A process for producing a heterocyclic compound of the generalformula: ##STR6## or a salt thereof characterized by reacting a compoundof the general formula: ##STR7## or a salt thereof with a compound ofthe general formula:

    R.sup.1 -Q.sup.2                                           (III)

or a salt thereof (wherein Q¹ and Q² are such that either one of them is--NH₂ with the other being --NCO; the other symbols have the meaningsdefined above);

(3) A process for producing a heterocyclic compound of the generalformula: ##STR8## wherein all the symbols have the meanings definedabove, or a salt thereof characterized by reacting a compound of thegeneral formula: ##STR9## wherein all the symbols have the meaningsdefined above, or a salt thereof with a compound of the general formula:

    R.sup.1 --Y.sup.1 --COOH                                   (VI)

wherein Y¹ means a bond, an C₁ or 2 alkylene group or--CH═CH--; and R¹has the meaning defined above, or a reactive derivative thereof; and

(4) An acyl-CoA:cholesterol acyltransferase inhibitor compositioncontaining a heterocyclic compound of formula (I) or a salt thereof.

Referring to the above general formulas, rings A and B each mean abenzene ring which may optionally be substituted. The substituents mayinclude, among others, halogen atoms, alkyl groups which may behalogenated, alkoxy groups which may be halogenated, alkylthio groupswhich may be halogenated, C₁₋₃ acyloxy groups (such as formyloxy,acetoxy, propionyloxy, etc.), di-alkylamino groups, and hydroxy.Examples of said halogen as substituents are fluorine, chlorine, bromineand iodine. Among the alkyl groups which may be halogenated arestraight-chain or branched alkyl groups of 1 to 6 carbon atoms and thecorresponding groups substituted by 1 to 5 halogen atoms such as thosementioned above, thus being exemplified by methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl,isobutyl, sec-butyl, tertbutyl, pentyl, isopentyl, neopentyl,5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl,6,6,6-trifluorohexyl, 5-trifluoromethylpentyl and so on. The alkoxygroups which may be halogenated or the alkylthio groups which may behalogenated may for example be the optionally halogenated groups formedupon addition of one oxygen atom or one sulfur atom to any of theaforementioned alkyl or haloalkyl groups. Thus, such optionallyhalogenated alkoxy groups as methoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxy, etc.,and such optionally halogenated alkylthio groups as methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio, etc. can be mentioned as preferred examples. As thedi-alkylamino groups, such di-C₁₋₆ alkylamino groups as dimethylamino,diethylamino, dipropylamino, diisopropylamino, methylethylamino, etc.can be used as preferred examples.

The substituents on rings A and B may be present in any optionalposition or positions of each ring and where two or more substituentsare present, they may be the same or different. The number ofsubstituents may range from 1 to 4. Preferred examples of substitutedring A are benzene rings substituted by a halogen atom, e.g. fluorine orchlorine, an C₁₋₄ alkyl group such as methyl or ethyl, an C₁₋₄ alkoxygroup such as methoxy, ethoxy or the like, or an C₁₋₄ alkylthio groupsuch as methylthio or the like in position-2.

Referring further to the above formulas, R¹ means a hydrocarbon groupwhich may optionally be substituted. The hydrocarbon group R^(l)includes, among others, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl andaralkyl groups. The alkyl group R¹ is preferably a straight-chain orbranched alkyl group of 1 to 8 carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, heptyl, octyl and so on. The cycloalkylgroup R¹ is preferably a C₃₋₇ cycloalkyl group, such as cyclopropyl,cyclopentyl, cyclohexyl and so on. The cycloalkyl-alkyl group R¹ ispreferably a C₃₋₇ cycloalkyl-C₁₋₄ alkyl group such as cyclopropylmethyl,cyclohexylmethyl, and so on. The aryl group R¹ is preferably an C₆₋₁₀aryl group such as phenyl, naphthyl or the like. The aralkyl group R¹ ispreferably an C₇₋₁₆ aralkyl group such as phenyl-C₁₋₄ alkyl, e.g.benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl,3-phenylpropyl, diphenylmethyl and so on. These alkyl, cycloalkyl,cycloalkyl-alkyl, aryl and aralkyl groups represented by R¹ may eachhave 1 to 5 substituents which may be the same or different. Thesesubstituents may be preferably those mentioned for rings A and B, aswell as the following.

The aryl group R¹ is preferably phenyl and this phenyl group may have 1to 5 substituents such as halogen, alkyl, alkoxy, di-alkylamino,hydroxy, and hydroxy acylated by C₁₋₃ acyl, and particularly preferablyphenyl groups having 1 to 5 halogen atoms (e.g. fluorine, chlorine,bromine and iodine), particularly chlorine and/or fluorine atoms. Aspecific preferred example is 2,4-difluorophenyl. The preferred alkylgroups which may be attached to said phenyl group include C₁₋₄ alkylssuch as methyl, ethyl, isopropyl, etc., and more preferably2,6-dimethyl, 2,6-diethyl, 2-methyl-6-isopropyl and 2,6-diisopropyl. Thepreferred alkoxy groups which may be attached to said phenyl group areC₁₋₄ alkoxy groups such as methoxy, ethoxy and so on. As thedi-alkylamino groups which may be attached to said phenyl group, suchdi-C₁₋₆ alkylamino groups as dimethylamino, diethylamino, dipropylamino,etc. can be used as preferred examples, and more preferred examples are4-dimethylamino, etc. Furthermore, phenyl groups having one or moremembers of said C₁₋₄ alkyl groups or C₁₋₄ alkoxy groups in combinationwith hydroxy or hydroxy acylated by C₁₋₃ acyl (for example, formyl,acetyl, etc.), such as 4-acetoxy-3,5-dimethylphenyl,4-hydroxy-3,5-dimethylphenyl, 4-acetoxy-3,5-dimethoxyphenyl, and4-hydroxy-3,5-dimethoxyphenyl groups are preferred for R¹.

The aralkyl group R¹ is preferably benzyl, 1-phenylethyl or the like,and it is preferable that the benzene ring of such groups has 1 to 5substituents such as halogen, alkyl, alkoxy, di-alkylamino hydroxyand/or C₁₋₃ acylated hydroxy. The halogen mentioned just above ispreferably fluorine or chlorine. Thus, fluorine-substituted aralkylgroups are preferred and 2,4-difluorobenzyl is most desirable. The alkylgroups which may be present as substituents on the benzene ring ofbenzyl, 1-phenylethyl and other groups are C₁₋₄ alkyls such as methyl,ethyl, isopropyl and tert-butyl, to name but a few preferred examples.The alkoxy groups which may be present on the benzene ring of benzyl,1-phenylethyl, etc. are preferably C₁₋₄ alkoxy groups such as methoxy,ethoxy and so on. As the dialkylamino groups which may be present assubstituents on the benzene ring, such di-C₁₋₆ alkylamino groups asdimethylamino, diethylamino, dipropylamino, etc. can be used aspreferred examples. Particularly preferred examples of R¹ are benzylgroups having such C₁₋₄ alkoxy groups in combination with hydroxy orhydroxy acylated by C₁₋₃ acyl (e.g. formyl, acetyl, etc.). Thus, R¹ ispreferably 4-acetoxy-3,5-dimethylbenzyl, 4-hydroxy-3,5-dimethylbenzyl,4-acetoxy-3,5-dimethoxybenzyl, or 4-hydroxy-3,5-dimethoxybenzyl, forinstance.

In the above formulas, X means a group of the formula: ##STR10## (R² ishydrogen, alkyl or alkoxy; m is equal to 0 or 1), the formula: ##STR11##(R³ is hydrogen or alkyl) or the formula: --O--CO--. The alkyl groupsrepresented by R² and R³ include straight-chain or branched groups of 1to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl andso on.

The alkoxy group R² includes, among others, straight-chain or branchedalkoxy groups of 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,isopentyloxy, neopentyloxy, hexyloxy and so on.

The formula: ##STR12## means that, where m=1, the nitrogen atom is inthe form of N-oxide.

Preferred examples of X are --N=CH--, ##STR13## and so on.

In the above formulas, Y means a bond, --NH--, an C₁ or 2 alkylene groupor --CH═CH--. The C₁ or 2 alkylene group may for example be --CH₂ --,--CH₂ CH₂ -- or ##STR14##

Preferred examples of Y are --NH--, --CH₂ --, --CH₂ CH₂ -- and--CH═CH--. The symbol n means a whole number of 3 to 6, preferably 3 or4.

The heterocyclic compound of formula (I) or a salt thereof can beproduced by the following and other processes.

In the first place, compound (IV), which is the compound (I) whereinY=--NH--, can be produced by reacting compound (II) or a salt thereofwith compound (III) or a salt thereof. Thus,

Process (1):

A compound of the general formula: ##STR15## wherein all the symbolshave the meanings defined hereinbefore, is reacted with a compound ofthe general formula:

    R.sup.1 --NH.sub.2                                         (IX)

wherein the symbol has the meaning defined hereinbefore, or a saltthereof to give compound (IV) or a salt thereof. Alternatively, Process(2):

A compound of the general formula: ##STR16## wherein all the symbolshave the meanings defined hereinbefore, or a salt thereof is reactedwith a compound of the general formula:

    R.sup.1 --NCO                                              (X)

wherein the symbol has the meaning defined hereinbefore, to givecompound (IV) or a salt thereof.

Process (3):

Compound (VII), which is the compound (I) wherein Y means a bond, C₁ or2 alkylene or --CH═CH--, or a salt thereof can be produced by reactingcompound (V) or a salt thereof with compound (VI) or a reactivederivative thereof.

Process (4):

Furthermore, compound (I) wherein Y=--CH₂ CH₂ -- or a salt thereof canbe produced by reducing compound (I) wherein Y=--CH=CH-- or a saltthereof.

Each of the above processes (1) through (4) is now described in furtherdetail.

Process (1): The reaction between compound (VIII) and compound (IX) or asalt thereof (e.g. salts with mineral acids such as hydrochloric acid,sulfuric acid, etc. or salts with organic acids such as methanesulfonicacid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaricacid, maleic acid, etc.) is generally conducted in a solvent. Thesolvent may be any solvent that will not interfere with the reaction,such as ethers (e.g. ethyl ether, isopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane, etc.), aromatic hydrocarbons (e.g. benzene,toluene, xylene, etc.), esters (e.g. methyl acetate, ethyl acetate,etc.), N,N-dimethylformamide, dimethyl sulfoxide, etc., to name but afew preferred examples. When compound (IX) is used in the form of asalt, the reaction can be advantageously conducted in the presence of anacid acceptor where necessary. The acid acceptor useful for this purposeincludes tertiary amines such as trimethylamine, triethylamine,N-methylmorpholine, etc. and aromatic amines such as pyridine, picoline,N,N-dimethylaniline and so on. The proportion of such amine is 1 to 5mole equivalents, preferably 1 to 3 mole equivalents, to each mole of asalt of compound (IX). The reaction temperature is generally --10 ° C.to 180° C. and preferably 0° C. to 120° C. The reaction time isgenerally 15 minutes to 40 hours and preferably 30 minutes to 20 hours.The proportion of (IX) or a salt thereof is 1 to 5 mole equivalents,preferably 1 to 3 mole equivalents, to each mole of (VIII).

Process (2): The reaction between compound (V) or a salt thereof (e.g.salts with mineral acids such as hydrochloric acid, sulfuric acid, etc.or salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid,maleic acid, etc.) and compound (X) is carried out under the sameconditions as in Process (1) described above. When (V) is used in theform of a salt, an acid acceptor similar to that mentioned for Process(1) is employed. The proportion of compound (X) is generally 1 to 5 moleequivalents and preferably 1 to 3 mole equivalents to each mole of (V).

Process (3): The reaction between compound (V) or a salt thereof (e.g.salts with mineral acids such as hydrochloric acid, sulfuric acid, etc.or salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid,maleic acid, etc.) and compound (VI) is generally carried out in thepresence of an appropriate condensing agent or by the procedure ofconverting (VI) to a reactive derivative and, then, reacting it with (V)or a salt thereof. The condensing agent mentioned above includes, amongothers, dicyclohexylcarbodiimide (DCC), diethyl phosphorocyanidate(DEPC), diphenylphosphoryl azide (DPPA) and so on. When such acondensing agent is employed, generally the reaction is conducted withadvantage in a solvent (e.g. tetrahydrofuran, dioxane, dimethoxyethane,ethyl acetate, benzene, toluene, N,N-dimethylformamide, dimethylsulfoxide, etc.). This reaction may be hastened by conducting it in thepresence of a base and is carried out generally at--10° C. to 100° C.and preferably at about 0° C. to 60° C. The reaction time is generally 1to 96 hours and preferably 1 to 72 hours. The proportions of (VI) andcondensing agent are 1 to 5 mole equivalents each, preferably 1 to 3mole equivalents each, to each mole of (v) or a salt thereof. The basemay for example be an alkylamine such as triethylamine or a cyclic aminesuch as N-methylmorpholine, pyridine and so on. The proportion of thebase is 1 to 5 mole equivalents, preferably 1 to mole equivalents, toeach mole of compound (V) or a salt thereof. The reactive derivative of(VI) includes, among others, the corresponding acid halides (e.g.chloride, bromide, etc.), acid anhydride, mixed acid anhydride (e.g.anhydrides with methyl carbonate, ethyl carbonate, isobutyl carbonate,etc.), active esters (e.g. ester with hydroxysuccinimide, ester with1-hydroxybenzotriazole, ester withN-hydroxy-5-norbornene-2,3-dicarboximide, ester with p-nitrophenol,ester with 8-hydroxyquinoline, etc.) and so on. Particularly preferredare acid halides. The reaction between compound (V) or a salt thereofand such a reactive derivative of (VI) is generally conducted in asolvent (e.g. chloroform, dichloromethane, ethyl ether, tetrahydrofuran,dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, pyridine,N,N-dimethylformamide, etc.). This reaction may be hastened byconducting it in the presence of a base and is generally conducted at--10° C. to 120° C. and preferably at 0° C. to 100° C. The reaction timeis generally 1 to 48 hours and preferably 1 to 24 hours. The proportionof the reactive derivative of (VI) is 1 to 5 mole equivalents,preferably 1 to 3 mole equivalents, to each mole of (V) or a saltthereof. The base mentioned above includes, among others, alkylaminessuch as triethylamine, etc., cyclic amines such as N-methylmorpholine,pyridine, etc., aromatic amines such as N,N-dimethylaniline,N,N-diethylaniline, etc., alkali metal carbonates such as sodiumcarbonate, potassium carbonate, etc., and alkali metal hydrogencarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and so on. The proportion of the base is 1 to 5 moleequivalents, preferably 1 to 3 mole equivalents, to each mole ofcompound (V) or a salt thereof. When a water-immiscible solvent isemployed, water may be added to the reaction system so as to conduct thereaction in a binary phase.

Process (4): Compound (I) wherein Y=--CH=CH-- or a salt thereof can bereduced to compound (I) wherein Y=--CH₂ CH₂ -- or a salt thereof.

The reducing agent which can be used for this purpose includes, amongothers, metal hydride complexes such as lithium aluminum hydride, sodiumborohydride, lithium borohydride and so on. The proportion of thereducing agent is generally 0.5 to 5 mole equivalents, preferably 0.5 to2 mole equivalents, to each mole of compound (I) [Y=--CH=CH--] or a saltthereof. This reaction is generally conducted in a solvent (e.g.methanol, ethanol, ethyl ether, tetrahydrofuran, dioxane, etc.). Thereaction temperature is generally -5° C. to 120° C. and preferably 0° C.to 100° C. The reaction time is generally 30 minutes to 12 hours andpreferably 30 minutes to 6 hours.

Instead of using the reducing agent mentioned above, this reductionreaction can be carried out using a metal in combination with an acid ora metal in combination with a base or an alcohol. When the metalmentioned just above is zinc, tin or iron, for instance, an acid (e.g.hydrochloric acid, sulfuric acid, acetic acid, etc.) is chiefly used asthe hydrogen source. When the metal is potassium, sodium, lithium or thelike, the hydrogen source is usually a base (e.g. ammonia, methylamine,dimethylamine, ethylamine, diethylamine, etc.) or an alcohol (e.g.methanol, ethanol, propanol, etc.). The proportion of the metal for thepurposes of this reaction is 1 to 10 mole equivalents, preferably 1 to 5mole equivalents, to each mole of compound (I) [Y=--CH=CH--] or a saltthereof. This reaction is generally conducted in a solvent (e.g. analcohol such as methanol, ethanol, etc. or an ether such astetrahydrofuran, dioxane, dimethoxyethane, etc.), although the acid orbase used may be allowed to double as a solvent. The reactiontemperature is generally 0° C. to 120° C. and preferably 0° C. to 80° C.The reaction time is generally 30 minutes to 12 hours and preferably 30minutes to 6 hours.

This reduction reaction may also be carried out by the catalyticreduction method. The catalyst used for this purpose includes, amongothers, palladium black, palladium-on-carbon, platinum oxide, platinumblack, Raney nickel, rhodium-on-carbon and so on. The reaction isgenerally conducted in a solvent (e.g. methanol, ethanol, isopropylalcohol, tetrahydrofuran, dioxane, dimethoxyethane, formic acid, aceticacid, N,N-dimethylformamide, etc.). This reaction is conducted generallyat atmospheric pressure to 20 atmospheres, preferably atmosphericpressure to 5 atmospheres. The reaction temperature is generally 0° C.to 100° C. and preferably 0° C. to 80° C. The reaction time is generally30 minutes to 24 hours and preferably 30 minutes to 12 hours.

Where a lower alkoxy group is present on the benzene ring of thecompound (I) or salt thereof thus produced by any of Processes (1)through (4) described hereinbefore, it can be converted to a hydroxygroup, where necessary, by reacting the compound with boron trifluorideor the like. This reaction is generally carried out in a solvent (e.g.dichloromethane, chloroform, carbon tetrachloride, benzene, toluene,etc.) at a temperature of about --20° C. to 80° C., preferably about 0°C. to 30° C., using boron trifluoride in a proportion of about 1 to 10mole equivalents, preferably about 1 to 5 mole equivalents, per loweralkoxy group. The reaction time is generally 15 minutes to 24 hours andpreferably 30 minutes to 12 hours.

Where an acyloxy group is present on the benzene ring of the compound(I) or salt thereof thus produced by any of Processes (1) through (4)described hereinbefore, it can be converted to a hydroxy group, wherenecessary, by hydrolyzing the compound. This reaction is generallycarried out in a solvent (e.g., methanol, ethanol, propanol,tetrahydrofuran, dioxane, dimethoxyethane, aceton,N,N-dimethylformamide, etc.) in the presence of a base (e.g., ammonia,methylamine, ethylamine, dimethylamine, potassium carbonate, sodiumcarbonate, potassium hydroxide, sodium hydroxide, etc.) or an acid(e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). Thereaction temperature is generally -10° C. to 100° C. and preferably 0°C. to 80° C. The reaction time is 10 minutes to 40 hours, preferably 15minutes to 30 hours. The used amount of the base or acid is 1 to 200mole equivalents, preferably 1 to 100 mole equivalents, to each mole ofthe starting material acyloxy derivative. This reaction may be carriedout in a mixture of water and such a solvent as mentioned above.

Where a hydroxy group is present on the benzene ring of the compound (I)or salt thereof obtained by any of Processes (1) through (4) describedhereinbefore, it can be converted to an alkoxy group or an acyloxygroup, where necessary, by alkylating or acylating the compound as thecase may be. The alkylation reaction is carried out using an alkylatingagent such as optionally substituted alkane halides (e.g. chloride,bromide, iodide, etc.), sulfuric esters or sulfonic esters (e.g.methanesulfonates. p-toluenesulfonates, benzenesulfonates, etc.) in asolvent (e.g. methanol, ethanol, propanol, dimethoxyethane, dioxane,tetrahydrofuran, aceton, N,N-dimethylformamide, etc) in the presence ofa base (e.g. an organic base such as trimethylamine, triethylamine,N-methylmorpholine, pyridine, picolin, N,N-dimethylaniline, an inorganicbase such as potassium carbonate, sodium carbonate, potassium hydroxide,sodium hydroxide, etc.). The reaction temperature is generally -10° C.to 100° C. and preferably about 0° C. to 80° C. The proportion of suchan alkylating agent is about 1 to 5 mole equivalents, preferably about 1to 3 mole equivalents, to each mole of the staring material phenolicderivative. The reaction time is generally 15 minutes to 24 hours andpreferably 30 minutes to 12 hours.

The reaction for acylating the hydroxy group on the benzene ring iscarried out using a selected carboxylic acid or a reactive derivativethereof. While it depends on the kind of the acylating agent and of thestarting material phenolic derivative, this reaction is generallyconducted in a solvent (e.g. benzene, toluene, ethyl ether, ethylacetate, chloroform, dichloromethane, dioxane, tetrahydrofuran,N,N-dimethylformamide, pyridine, etc.). For hastening the reaction, thereaction may be conducted in the presence of an appropriate base (e.g.sodium hydrogen carbonate, potassium hydrogen carbonate, sodiumcarbonate, potassium carbonate, sodium acetate, triethylamine, pyridine,etc.). The reaction derivative of such carboxylic acid includes, amongothers, the acid anhydride, mixed acid anhydrides, and acid halides(e.g. acid chloride, acid bromide, etc.) mentioned above. The proportionof such acylating agent is 1 to 5 mole equivalents, preferably 1 to 3mole equivalents, to each mole of the starting material phenolicderivative. The reaction temperature is generally 0° C. to 150° C. andpreferably about 10° to 100° C. The reaction time is 15 minutes to 12hours and preferably 30 minutes to 6 hours.

When compound (I) is obtained in the free form by any of the processesdescribed hereinbefore, it can be converted to a salt in the per seconventional manner, using a mineral acid (e.g hydrochloric acid,sulfuric acid, hydrobromic acid, etc.) or an organic acid (e.g.methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalicacid, fumaric acid, maleic acid, tartaric acid, etc.). When the productcompound (I) is a salt, it can be converted to the free compound or adesired other salt in the per se conventional manner.

The resulting object compound (I) or salt thereof can be purified andisolated by the per se known separation and purification procedures(e.g. concentration, solvent extraction, column chromatography,recrystallization, etc.).

The compound (I) or pharmaceutically acceptable salt thereof hasexcellent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitoryactivity and is moderate in acute and chronic toxicity. ACAT is theenzyme involved in higher fatty acid esterification of cholesterol inthe cell and is known to play an important role in the absorption ofcholesterol esters in the small intestine. Therefore, an inhibitor ofACAT can inhibit the absorption of dietary cholesterol from theintestinal tract and suppress increases in the blood cholesterol levelas well as the accumulation of intracellular cholesterol in thearteriosclerotic focus to thereby arrest progression of atheroscleroticchanges. The compound (I) or salt of the present invention which hasexcellent ACAT inhibitory activity is, therefore, of value as a safeprophylactic and therapeutic drug for hypercholesterolemia andatherosclerosis and various diseases associated therewith (e.g. ischemicheart diseases such as myocardial infarction and cerebrovasculardisorders such as cerebral infarction and cerebral apoplexy) inmammalian animals (such as the mouse, rat, hamster, rabbit, cat, dog,horse, cattle, sheep, monkey and man).

Furthermore, among species of compound (I) and salts thereof are thosecompounds which inhibit production of lipid peroxides (antioxidantactivity). It is known that the peroxidation of lipids in the body isassociated, in a large measure, with the onset of arteriosclerosis andischemic diseases of the brain and cardiovascular system. Therefore, thecompound (I) or salt having ACAT inhibitory activity and antioxidantactivity in common is particularly useful as a drug with which variousassociated vascular lesions can be prevented or treated from both theaspect of blood cholesterol and that of lipid peroxide.

When the compound of general formula (I) or a pharmaceuticallyacceptable salt thereof is used as the drug mentioned above, it can beformulated with a vehicle, excipient or diluent to provide a powder,granule, tablet, capsule, injection or the like for oral or parenteraladministration. For use as an inhibitor of absorption of cholesterol,however, it is preferably administered orally. While the proper dosagedepends on the kind of compound (I) or salt thereof, the route ofadministration chosen, and the condition and age of the patient, amongother factors, the recommended dosage for oral administration to adultpatients with hypercholesterolemia, for instance, is about 0.005-50 mg,preferably about 0.05-10 mg and, for still better results, about 0.2 to4 mg/kg body weight/day, which daily dosage is preferably administeredin 1-3 divided doses.

The starting compound (V) or (VIII) for the production of the compound(I) or salt according to the invention can be prepared with commercialadvantage by the processes described below or any other processesanalogous thereto. ##STR17## In the above formulas, R^(3') and R⁴ eachmeans an alkyl group; X' means --NHCO--, ##STR18## Z means a leavinggroup; the other symbols are as defined hereinbefore. ##STR19## In theabove formulas, R⁵ and R⁶ are the same or different and each means analkyl group, a phenyl group or a benzyl group or R⁵ and R⁶, takentogether with the adjacent nitrogen atom, form a ring; the other symbolsare as defined hereinbefore. ##STR20## In the above formulas, R^(2')means a hydrogen atom or an alkyl group; R⁷ means an alkyl group; theother symbols are as defined hereinbefore. ##STR21## In the aboveformulas, R⁸ means an alkyl group or an aralkyl group; the other symbolsare as defined hereinbefore.

[Process A]

In this process, compound (XIV) can be produced by reacting an2-aminobenzophenone derivative (XI) with a malonic diester (XV) orreacting (XI) with compound (XII), followed by cyclization withelimination of water in the presence of a base. The reaction between(XI) and (XV) to give (XIV) is generally conducted under heating in theabsence of a solvent. Preferably this reaction is conducted in thepresence of an amine (such as piperidine, pyrrolidine, triethylamine,1,5-diazabicyclo[4,3,0]non-5-ene (DBN),1,8-diazabicyclo[5,4,0]-7-undecene (DBU), 1,4-diazabicyclo[2,2,2]octane(DABCO), etc., potassium fluoride, cesium fluoride, tetrabutylammoniumfluoride or the like. The reaction temperature is generally about 60° C.to 250° C. and preferably 80° C. to 220° C. The reaction time isgenerally about 30 minutes to 60 hours and preferably 1 to 24 hours. Theproportion of (XV) is about 1 to 5 mole equivalents, preferably 1 to 3mole equivalents to each mole of (XI). The reaction between (XI) and(XII) is generally carried out in a solvent (e.g. ethers such as ethylether, tetrahydrofuran, dioxane, dimethoxyethane, etc., aromatichydrocarbons such as benzene, toluene, xylene, etc., esters such asmethyl acetate, ethyl acetate, etc., halogenated hydrocarbons such asdichloromethane, chloroform, etc., pyridine, dimethylformamide, etc.),where necessary in the presence of a base (e.g. triethylamine, pyridine,potassium carbonate, sodium carbonate, potassium hydrogen carbonate,sodium hydrogen carbonate, etc.). Where necessary, this reaction may beconducted in a solvent mixture containing water. The reactiontemperature is generally about -20° C. to 150° C. and preferablyabout--10° C. to 120° C. The reaction time is generally about 10 minutesto 12 hours and preferably 20 minutes to 8 hours. The proportion of(XII) is about 1 to 5 mole equivalents, preferably about 1 to 3 moleequivalents to each mole of compound (XI). The product compound (XIII)is cyclized using a base to give compound (XIV). This reaction isgenerally conducted in a solvent (e.g. methanol, ethanol, t-butanol,benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane,dimethylformamide, etc.) in the presence of a base (e.g. potassiumt-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, potassiumhydride, piperidine, pyrrolidine, triethylamine, DBN, DBU, DABCO, etc.).The reaction temperature is generally about 0° C. to 200° C. andpreferably 20° C. to 170° C. The reaction time is generally about 30minutes to 12 hours and preferably 1 to 8 hours. The proportion of thebase is about 0.01 to 3 mole equivalents, preferably 0.05 to 2 moleequivalents, to each mole of (XIII). Where necessary, the reaction maybe hastened by removing the water constantly from the reaction systemwith a Dean-Stark apparatus.

The reaction between compounds (XIV) and (XVII) gives rise to theN-alkyl compound (XVIII) and/or O-alkyl compound (XIX). This reaction isgenerally conducted in a solvent (e.g. alcohols such as methanol,ethanol, etc., ethers such as tetrahydrofuran, dioxane, dimethoxyethane,etc., ketones such as acetone, 2-butanone, etc., dimethylformamide,dimethyl sufloxide, etc.) in the presence of a base (e.g. sodiumhydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide,potassium t-butoxide, sodium hydride, sodium amide, potassium carbonate,sodium carbonate, triethylamine, DBU, etc.). Generally this reactiongives rise to a mixture of (XVIII) and (XIX), which can be separated byrecrystallization or chromatography. Depending on the kind of (XVII) andof the solvent or the reaction temperature chosen, either of them can beselectively produced with preference. The reaction temperature isgenerally about -5° C. to 150° C. and preferably about 0° C. to 100° C.,and the reaction time is generally about 30 minutes to 30 hours andpreferably about 1 to 15 hours. The proportions of (XVII) and the baseare 1 to 5 mole equivalents each, preferably 1 to 2 mole equivalentseach, based on compound (XIV).

Then, (XIV), (XVIII) and (XIX) are hydrolyzed to (XVI), (XX) and (XXI),respectively. These reactions may be conducted generally in a solvent(e.g. alcohols such as methanol, ethanol, propanol, etc., ethers such astetrahydrofuran, dioxane, diemthoxyethane, etc., or mixtures thereof),using the hydroxide of an alkali or alkaline earth metal, such as sodiumhydroxide, potassium hydroxide, barium hydroxide and so on. The reactiontemperature is generally about 0° C. to 120° C. and preferably about 15°C. to 100° C. The reaction time is about 15 minutes to 36 hours,preferably about 15 minutes to 20 hours. This hydrolysis reaction can beconducted under acidic conditions as well. The acid for this purpose maybe a mineral acid (e.g. hydrochloric acid, sulfuric acid, phosphoricacid, hydrobromic acid, etc.) or an organic acid (e.g. formic acid,acetic acid, propionic acid, p-toluenesulfonic acid, trifluoroaceticacid, etc.). In some cases, a mixture of such acids may be employed.This reaction can be carried out using a solvent (e.g. methanol,ethanol, propanol, isopropyl alcohol, dioxane, tetrahydrofuran,methoxyethanol, dimethoxyethane, etc.). The reaction temperature isgenerally 20° C. to 180° C. and preferably 20° C. to 150° C. Thereaction time is generally 10 minutes to 60 hours and preferably 20minutes to 40 hours.

Then, the carboxylic acid (XVI), (XX) or (XXI) is converted to thecorresponding acid azide. While many reaction techniques are describedin the literature, any of them can be applied to compounds (XVI), (XX)and (XXI) in the instant process. For example, the acid azide of (XVI),(XX) or (XXI) can be synthesized by using diphenylphosphoryl azide(DPPA) as the azidating agent. This reaction can be generally conductedin a solvent inert to the reaction (e.g. ethers such as ethyl ether,isopropyl ether, dmethoxyethane, tetrahydrofuran, dioxane, etc.,aromatic hydrocarbons such as benzene, toluene, xylene, etc., esterssuch as methyl acetate, ethyl acetate, etc., ketones such as acetone,2-butanone, etc., pyridine, N,N-dimethylformamide, etc.). The reactionmay be hastened by conducting it in the presence of a base (e.g.trimethylamine, triethylamine, N-methylmorpholine, etc.). The reactiontime is generally about 5 minutes to 12 hours and preferably about 10minutes to 6 hours. The reaction temperature is generally about -10° C.to 150° C. and preferably about -5° C. to 120° C. The proportion of DPPAis 1 to 3 mole equivalents, preferably 1 to 2 mole equivalents, to eachmole of (XVI), (XX) or (XXI).

The acid azide thus obtained can be isolated and purified by the per seknown procedure but is generally converted to the isocyanate (VIII') byheating the reaction mixture as such without isolating. Thistransformation reaction is preferably conducted in the same solvent asused for the azidation and is generally carried out at about 20° C. to200° C. and preferably at about 30° C. to 150° C. The reaction time isgenerally about 5 minutes to 10 hours and preferably about 5 minutes to6 hours. The product compound (VIII') can be isolated by the per seknown procedure but the reaction mixture may be directly used for theproduction of compound (I) or used as a staring material for theproduction of (V'). Thus, this compound (VIII') can be hydrolyzed tocompound (V'). This hydrolysis reaction can be conducted undersubstantially the same conditions as the hydrolysis of compounds (XIV),(XVIII) and (XIX) to compounds (XVI), (XX) and (XXI).

[Process B]

The alkyl group, represented by R⁵ and R⁶, is preferably an alkyl groupof 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl andbutyl. R⁵ and R⁶ may, taken together with the adjacent nitrogen atom,constitute a ring. Examples of such ring are 5- to 7-menbered rings suchas pyrrolidine, piperidine, homopiperidine and so on. These rings mayhave still another oxygen atom, the morpholine ring being an example.

Compound (XI) is reacted with compound (XXII) or (XXIII) to givecompound (XXIV). This reaction is generally conducted in a solvent (e.g.esters such as methyl acetate, ethyl acetate, etc., ketones such asacetone, 2-butanone, etc., and aromatic hydrocarbons such as benzene,toluene, etc.) in the presence of an acid. The acid includes, amongothers, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand so on, and such acid can be used in anhydrous condition or in theform of an aqueous solution. The reaction may be conducted in ahomogeneous phase or in a binary phase consisting of the solvent andwater. The proportion of (XXII) or (XXIII) is about 1 to 10 moleequivalents, preferably about 1 to 5 mole equivalents, to each mole of(XI). The acid is used in a proportion of about 1 to 300 moleequivalents, preferably about 5 to 100 mole equivalents, based on (XI).The reaction temperature is generally about 0° C. to 120° C. andpreferably about 10° C. to 100° C. The reaction time is about 30 minutesto 15 hours, preferably about 30 minutes to 10 hours. Then, compound(XXIV) is cyclized in the presence of a base to give (XXV). Thiscyclization reaction can be conducted under the same or substantiallysame conditions as the synthesis of (XIV) from (XIII) in Process A.Furthermore, this compound (XXV) is reduced to (V"). The reducing agentfor this purpose includes lithium aluminum hydride, lithium borohydrideand so on, and its proportion to (XXV) is about 0.5 to 10 moleequivalents and preferably about 1 to 5 mole equivalents. This reactionis generally carried out in a solvent (e.g. methanol, ethanol, ethylether, tetrahydrofuran, dioxane, dimethoxyethane, etc.). The reactiontemperature is generally about -5° C. to 120° C. and preferably about 0°C. to 100° C. The reaction time is generally about 15 minutes to 12hours and preferably 30 minutes to 8 hours.

Instead of using the above reducing agent, this reduction reaction canalso be conducted using a metal in combination with an acid, a metalsalt in combination with an acid, or a metal in combination with a base.The metal mentioned above includes, among others, zinc, tin and iron,while the metal salt may for example be tin(II) chloride. Here, thehydrogen source is an acid (e.g. hydrochloric acid, sulfuric acid,hydrobromic acid, acetic acid, etc.). When potassium, sodium, lithium orthe like is used as said metal, the hydrogen source is generally a base(e.g. ammonia, methylamine, dimethylamine, ethylamine, diethylamine,etc.), although an alcohol (e.g. methanol, ethanol, propanol, etc.) canalso be employed. The proportion of said metal or metal salt to (XXV) inthis reaction is about 1 to 20 mole equivalents, preferably about 1 to10 mole equivalents. The reaction is generally conducted in a solvent(e.g. alcohols such as methanol, ethanol, etc. and ethers such astetrahydrofuran, dioxane, dimethoxyethane, etc.), although the acid orbase as the hydrogen source may double as the solvent. The reactiontemperature is generally about 0° C. to 150° C. and preferably about 10°C. to 120° C. The reaction time is generally about 15 minutes to 12hours and preferably about 30 minutes to 10 hours.

The reduction reaction can also be conducted by the catalytic reductionmethod. The catalyst used for this purpose includes, among others,palladium black, palladium-on-carbon, platinum oxide, platinum black,Raney nickel, rhodium-on-carbon and so on. This reaction is generallyconducted in a sovlent (e.g. methanol, ethanol, isopropyl alcohol,tetrahydrofuran, dioxane, dimethoxyethane, formic acid, acetic acid,N,N-dimethylformamide, etc.). The reaction temperature is about 0° C. to120° C, preferably about 10° C. to 100° C. The reaction pressure isgenerally atmospheric pressure to 50 atmospheres and preferablyatmospheric pressure to 10 atmospheres.

[Process C]

The alkyl group R⁷ is preferably an alkyl group of 1 to 4 carbon atoms,such as methyl, ethyl, propyl, isopropyl and butyl.

Compound (XI) is reacted with compound (XXVI) to 10 give (XXVII). Thisreaction is generally conducted in a solvent (e.g. alcohols such asmethanol, ethanol, propanol, etc., ethers such as tetrahydrofuran,dioxane, dimethoxyethane, etc., aromatic hydrocarbons such as benzene,toluene, xylene, etc., and organic acids such as formic acid, aceticacid, propionic acid, etc.) but may be conducted in the absence of asolvent in the presence of an acid catalyst (e.g. hydrochloric acid,sulfuric acid, hydrobromic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc.). The proportion of (XXVI) to (XI) isabout 1 to 10 mole equivalents, preferably about 1 to 5 moleequivalents. The proportion of the said catalyst to (XI) is about 0.01to 2 mole equivalents, preferably about 0.05 to 1 mole equivalent. Thereaction temperature is generally about 0° C. to 200° C. and preferablyabout 10° C. to 150° C. The reaction time is generally about 15 minutesto 24 hours and preferably about 30 minutes to 15 hours. The productcompound (XXVII) is then converted to (XXVIII)→(VIII")→(V'"). Theprocedures and conditions of these reactions may be similar to thosedescribed for Process A.

[Process D]

The alkyl group R⁸ is preferably an alkyl group of 1 to 4 carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl andtert-butyl. The aralkyl group R⁸ is preferably benzyl.

Compound (XXIX) is reacted with compound (XV) to give (XXX). Thisreaction is conducted in a solvent (e.g. alcohols such as methanol,ethanol, propanol, etc., ethers such as tetrahydrofuran, dioxane,dimethoxyethane, etc., aromatic hydrocarbons such as benzene, toluene,xylene, etc., dimethylformamide, dimethyl sulfoxide, etc.) in thepresence of a base (e.g. pyrrolidine, piperidine, DBN, DBU, DABCO,sodium hydride, potassium tert-butoxide, sodium methoxide, etc.). Incertain instances, the reaction can be conducted in the presence of abase without employing a solvent to give (XXX). The reaction temperatureis generally 20° C. to 250° C. and preferably 50° C. to 220° C. Thereaction time is generally 30 minutes to 50 hours and preferably 1 to 24hours. The proportion of (XV) to (XXIX) is 1 to 10 mole equivalents,preferably 1 to 5 mole equivalents. The proportion of the base to (XXIX)is 0.01 to 3 mole equivalents, preferably 0.05 to 2 mole equivalents.The product (XXX) can be converted to (XXXI) and further to (VIII"") and(V""). The procedures and conditions of such reactions may be thosementioned for Process A.

The compound (VIII"") can be reacted with an alcohol (e.g. methanol,ethanol, propanol, tert-butanol, benzyl alcohol or the like) to givecompound (XXXII). This reaction is generally conducted using thecorresponding alcohol as a solvent, but a solvent system consisting ofsaid alcohol and a solvent such as ethers (e.g. tetrahydrofuran,dioxane, dimethoxyethane, etc.), aromatic hydrocarbons (e.g. benzene,toluene, xylene, etc.), N,N-dimethylformamide, pyridine, etc., may alsobe employed in certain instances. The reaction temperature is generallyabout 0° C. to 150° C. and preferably about 10° C. to 120° C. Thereaction time is 5 minutes to 12 hours, preferably 15 minutes to 10hours. The compound (XXXII) is hydrolyzed to (V""). This reaction can beconducted substantially under the same conditions as those of thehydrolysis reaction described for Process A.

The compound (XXXII) wherein R⁸ is a benzyl group is subjected tohydrogenolysis to yield (V'"). This reaction can be conducted by thesame catalytic reduction method as the preparation of (V") from (XXV) oran analogous one thereto.

The starting compounds (XI) and (XXIX) can be produced by the followingprocesses, for instance, or any processes analogous thereto. ##STR22##In the above formulas, R⁹ means an alkyl group or an aryl group; the thesymbols have the meanings defiend hereinbefore. ##STR23## In the aboveformulas, the symbols are as defiend hereinbefore.

Processes E and F are described in detail below.

[Process E]

The alkyl group R⁹ is preferably an alkyl group of 1 to 4 carbon atoms,such as methyl, ethyl, propyl, isopropyl and butyl. The aryl group R⁹ ispreferably phenyl, which may have substituents similar to thosementioned for ring A. The reaction between (XXXIII) and (XXXIV) to give(XXXV) is generally conducted in the presence of an appropriatecondensing agent (e.g. DCC, DEPC, DPPA, etc.) or alternatively using areactive derivative (e.g. acid chloride, acid bromide, acid anhydride,mixed acid anhydride, active ester, etc.) of (XXXIV). Of the abovereactive drivatives, the acid chloride and acid anhydride areparticularly preferred. The reaction conditions may be similar to thoseused in the production of (VII) from (V) and (VI). The (XXXV) is thenreacted with (XXXVI) to produce (XXXVII) in the presence of a Lewis acid(e.g. iron (III) chloride, zinc chloride, aluminum chloride, tintetrachloride, boron trifluoride, etc.) in a solvent inert to thereaction (e.g. dichloromethane, 1,2-dichloroethane, nitroethane,nitrobenzene, dichlorobenzene, etc.). Where necessary, the reaction maybe carried out by mixing (XXXV) and (XXXVI) with a Lewis acid in theabsence of a solvent. The reaction temperature is generally 0° C. to220° C. and preferably 50° C. to 180° C. The reaction time is generally20 minutes to 20 hours and preferably 30 minutes to 10 hours. Theproportions of (XXXVI) and Lewis acid to each mole of (XXXV) are 1 to 7mole equivalents each, preferably 1 to 3 mole equivalents each. Then,compound (XXXVII) is hydrolyzed to compound (XI). This hydrolysisreaction is preferably conducted under acidic conditions, using amineral acid such as sulfuric acid, hydrochloric acid, hydrobromic acidor the like. This reaction can be carried out using a mineral acid asthe solvent or, where necessary, acetic acid, ethylene glycol or thelike may be added to the reaction system for dissolving compound(XXXVII). The reaction temperature is generally about 50° C. to 200° C.and preferably 70° C. to 180° C. The proportion of the mineral acid to(XXXVI) is 5 to 500 mole equivalents, preferably 10 to 300 moleequivalents.

[Process F]

First, compound (XL) is synthesized from compound (XXXVIII) and compound(XXXIX) or a reactive derivative thereof. This reaction can be carriedout by the same procedure as, or a procedure analogous to, the proceduredescribed for the production of (XXXV) from (XXXIII) and (XXXIV) inProcess E. Then, compound (XXXIX) is produced from compound (XL). Thisreaction is conducted in a solvent (e.g. dichloromethane,1,2-dichloroethane, nitroethane, nitrobenzene, dichlorobenzene, etc.) inthe presence of a Lewis acid (e.g. iron (III) chloride, zinc chloride,aluminum chloride, tin tetrachloride, boron trifluoride, etc.). Wherenecessary, however, (XL) may be reacted with a Lewis acid in the absenceof a solvent. The reaction temperature is generally about 20° C. to 200°C. and preferably about 50° C. to 180° C. The reaction time is generally5 minutes to 8 hours and preferably 10 minutes to 6 hours. Theproportion of the Lewis acid to (XL) is 1 to 10 mole equivalents,preferably 1 to 5 mole equivalents.

The product compounds (XI) and (XXIX) can be isolated and purified bythe per se known procedures but the respective reaction mixtures as suchmay be used as starting materials in the next stages.

(e) Action

While the compound (I) and salt of the invention have excellent ACATinhibitory activity, pertinent pharmacologic test data are presentedbelow.

(1) Acyl-CoA:cholesterol transferase (ACAT) inhibitory activity

[Method]

Samples of ACAT enzyme were prepared from the small intestinal mucosalmicrosome fraction of a 6-week-old male sprague-Dawley rat fasted for 20hours in accordance with the procedure described by Heider et al,Journal of Lipid Research 24, 1127 (1982).

ACAT activity was determined in accordance with the method of Helgerudet al., Journal of Lipid Research 22, 271 (1981), by measuring theamount of labeled cholesterol ester produced from [1-¹⁴ C]oloyl-CoA andendogenous cholesterol.

[Results]

Table 1 shows the labeled cholesterol ester production inhibiting rate(%) at 10⁻⁶ M of the test compound as an indicator of ACAT inhibitoryactivity. The 50% inhibitory concentration (IC₅₀) determined by plottingat a plurality of concentration levels is also shown.

                  TABLE 1                                                         ______________________________________                                                        ACAT                                                          Test compound   inhibition                                                    (Example No.)   rate (%) IC.sub.50 (M)                                        ______________________________________                                         1              99.3     3.8 × 10.sup.-9                                 2              99.2     3.9 × 10.sup.-9                                 3              99.5     --                                                    4              91.5     --                                                    8              99.0     --                                                    9              94.6     --                                                   10              98.7     --                                                   11              75.6     --                                                   12              91.1     --                                                   13              89.9     --                                                   15              89.6     --                                                   16              94.4     --                                                   17              97.6     --                                                   18              86.9     --                                                   19              98.2     --                                                   ______________________________________                                    

Table 1 shows clearly that (I) or a salt thereof has very high ACATinhibitory activity.

(2) Plasma cholesterol lowering activity in cholesterol-fed rats

[Method]

Male Sprague-Dawley rats aged 7 weeks were divided into groups based onbody weight and put on a 1% cholesterol diet (the rat diet supplementedwith 0.5% cholic acid and 5% olive oil) containing 0.0003% of the testcompound for 7 days. The blood was sampled from surfeited rats between8:30 and 10:00 a.m. and the plasma cholesterol concentration wasenzymatically determined. The amount of the compound ingested wascalculated from the food consumption.

[Results]

                  TABLE 2                                                         ______________________________________                                                                 Plasma                                               Test compound Dose       cholesterol                                          Example No.   (mg/kg/day)                                                                              mg/dl                                                ______________________________________                                        Control group 0          181.8 ± 60.4                                      1             0.242 ± 0.012                                                                         80.8 ± 18.6*                                      2             0.227 ± 0.012                                                                         78.5 ± 10.2*                                      3             0.234 ± 0.014                                                                         78.1 ± 12.6*                                      ______________________________________                                         Each value is mean ± S.D.                                                  *p < 0.05 (ttest, against control group)                                 

It will be apparent from Table 2 that the test compounds significantlylowered the plasma cholesterol level under cholesterol loading. Table 2indicates, also, that compound (I) or a salt thereof has excellentplasma cholesterol lowering activity.

(f) Examples

The following reference and working examples are further illustrative ofthe present invention and should by no means be construed as definingthe metes and bounds of the invention.

The elution procedure in column chromatography in the reference andworking examples was performed under TLC (thin layer chromatography)monitoring. The TLC monitoring was performed using Merck's Silica Gel 60F₂₅₄ for the TLC plate, the column chromatographic eluent for thedeveloper solvent, and a UV detector for detection of spots. As thecolumn packing silica gel, the same Silica Gel 60 (70-230 mesh) fromMerck & Co. was used.

The symbols used in the working and reference examples have thefollowing meanings:

mg: milligram, g: gram, ml: milliliter, m.p.: melting point.

EXAMPLE 1

To a solution of3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline (2.5 g)in tetrahydrofuran (25 ml) was added 2,4-difluorophenyl isocyanate (1.2ml) dropwise and the mixture was stirred for 5 hours at roomtemperature. The solvent was then distilled off to give crystals ofN-[4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl]-N'-(2,4-difluorophenyl)urea.The crystals were collected by filtration and washed with isopropylether (3.42 g, 89.8%). Recrystallization from acetic acid-water gavecolorless needles, m.p. 247°-248° C.

Elemental analysis, for C₂₅ H₁₈ ClF₂ N₃ O Calcd.: C, 66.74; }t, 4.03; N,9.34 Found : C, 66.85; H, 3.97; N, 9.26

EXAMPLE 2

N-[7,8-Dihydro-4-(2-methylphenyl)-6H-cyclopenta[g]-quinolin-3-yl]-N'-(2,4-difluorophenyl)ureawas synthesized in the same manner as Example 1. Yield 86.5%, m.p.252°-254° C. (recrystallized from acetic acid-water)

Elemental analysis, for C₂₆ H₂₁ F₂ N₃ O Calcd.: C, 72.71; H, 4.93; N,9.78 Found: C, 72.61; H, 5.00; N, 9.67

EXAMPLE 3

Triethylamine (1.2 ml) was added dropwise to a mixture of4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylicacid (2.56 g), DPPA (2.64 g) and benzene (32 ml). The mixture wasstirred at room temperature for 30 minutes and, then, on reflux for 30minutes. Then, 2,4-difluoroaniline (1.0 ml) was added and the mixturewas further refluxed for 30 minutes. The reaction mixture was washedwith water, 1N HCl and water in the order mentioned and, then, dried(MgSO₄). The solvent was then distilled off to giveN-(2,4-difluorophenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]-benzopyran-3-yl]ureaas oil. The oil was crystallized by addition of isopropyl ether (3.4 g,95.2%). Recrystallization from acetone gave colorless prisms, m.p.223°-224° C.

Elemental analysis, for F₂₆ H₂₀ F₂ N₂ O₃ Calcd.: C, 69.95; H, 4.52; N,6.27 Found : C, 70.11; }I, 4.51; N, 6.20

EXAMPLE 4

To a mixture of 2,4-difluorophenylacetic acid (206 mg), DMF (1 drop) andtetrahydrofuran (4 ml) was added oxalyl chloride (0.13 ml) dropwise. Theresulting mixture was stirred at room temperature for 1 hour and thesolvent was then distilled off to give 2,4-difluorophenylacetylchloride. This chloride was dissolved in dichloromethane (5 ml) followedby addition of3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline (294mg) and N,N-dimethylaniline (0.13 ml). The mixture was further stirredat room temperature for 3 hours, after which it was washed with water,saturated aqueous solution of NaHCO₃ and water in the order mentionedand dried (over MgSO₄). The solvent was then distilled off to give4-(2-chlorophenyl)-3-(2,4-difluorophenylacetylamino)-7,8-dihydro-6H-cyclopenta(g)quinolineas oil. This oil was crystallized from isopropyl ether (yield 342 mg,76.3%). Recrystallization from ethanol gave colorless prisms, mp.179°-180° C.

Elemental analysis, for C₂₆ H₁₉ ClF₂ N₂ O Calcd.: C, 69.57; H, 4.27; N,6.24 Found : C, 69.57; H, 4.56; N, 6.31

EXAMPLE 5

By the procedure of Example 4, there was synthesized3-(4-acetoxy-3,5-dimethoxycinnamoylamino)-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline. Yield 44.0%,m.p. 155°-157° C. (as recrystallized from ethanol)

Elemental analysis, for C₃₁ H₂₇ ClN₂ O₅.C₂ H₅ OH Calcd.: C, 67.28; H,5.65; N, 4.76 Found : C, 67.01; H, 5.99; N, 4.62

EXAMPLE 6

By the procedure of Example 3, there was synthesizedN-(4-acetoxy-3,5-dimethylphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta-[g][1]benzopyran-3-yl]urea. Yield 82.8%, m.p. 248°-249° C. (recrystallizedfrom acetone)

Elemental analysis, for C₃₀ H₂₈ N₂ O₅ Found: C, 72.56; It, 5.68; N, 5.64Calcd.: C, 72.61; H, 5.63; N, 5.67

EXAMPLE 7

By the procedure of Example 3, there was synthesizedN-(4-acetoxy-3,5-dimethoxyphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta-[g] [1]benzopyran-3-yl]urea. Yield 77.7%, m.p. 233°-234° C. (asrecrystallized from ethanol-dichloromethane)

Elemental analysis, for C₃₀ H₂₈ N₂ O₇ Found: 68.17; H, 5.43; N, 5.30Calcd.: 68.00; H, 5.29; N, 5.07

EXAMPLE 8

By the procedure of Example 3, there was synthesizedN-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-yl]-N'-(2,4-difluorophenyl]urea. Yield 54.5%, m.p.240°-243° C. (as recrystallized from acetone)

Elemental analysis, for C₃₃ H₃₄ F₂ N₂ O₄.1/2H₂ O Calcd.: C, 69.58; H,6.19; N, 4.92 Found: C, 69.28; H, 6.14; N, 4.73

EXAMPLE 9

By the procedure of Example 3, there was synthesizedN-(4-dimethylaminophenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g] [1] benzo-pyran-3-yl]urea. Yield 73.3%, m.p. 154°-156° C. (as recrystallized fromacetone)

Elemental analysis, for C₂₈ H₂₇ N₃ O₃ Calcd.: C, 74.15; It, 6.00; N,9.26 Found : C, 74.10; II, 6.10; N, 9.17

EXAMPLE 10

By the procedure of Example 3, there was synthesizedN-(2,4-difluorophenyl)-N'-[4-(2-methylphenyl)-6,7,8,9-tetrahydro-2-oxo-2H-naphtho[2,3-b]pyran-3-yl]urea. Yield96.1%, m.p. 222°-223° C. (as recrystallized from acetone)

Elemental analysis, for C₂₇ H₂₂ F₂ N₂ O₃ Calcd.: C, 70.43; H, 4.82; N,6.08 Found : C, 70.75; H, 4.90; N, 6.03

EXAMPLE 11

By the procedure of Example 3, there was synthesizedN-(4-acetoxy-3,5-dimethylphenyl)-N'-[4-(2-chlorophenyl)-7,8-dihydro-2-methoxy-6H-cyclopenta[g]-quinolin-3-yl]urea.Yield 68.5%, m.p. 247°-248° C. (as recrystallized from acetone-hexane)

Elemental analysis, for C₃₀ H₂₈ ClN₃ O₄ Calcd.: C, 67.98; H, 5.32; N,7.93 Found : C, 67.80; H, 5.30; N, 7.91

EXAMPLE 12

By the procedure of Example 3, there was synthesizedN-(4-acetoxy-3,5-dimethylphenyl)-N'-[1-methyl-4-(2-methylphenyl)-2-oxo-l,2,7,8-tetrahydro-6H-cyclopenta[g]quinolin-3-yl]urea.Yield 80.6%, m.p. 178°-180° C. (as recrystallized from acetone-hexane)

Elemental analysis, for C₃₁ H₃₁ N₃ O₄ Calcd.: C, 73.06; H, 6.13; N, 8.25Found : C, 72.81; H, 6.33; N, 7.95

EXAMPLE 13

To a mixture of 3,4-dimethoxycinnamic acid (540 mg), DMF (2 drops) andtetrahydrofuran (10 ml) was added oxalyl chloride (0.27 ml) dropwise.The mixture was stirred at room temperature for 40 minutes, at the endof which time the solvent was distilled off to give3,4-dimethoxycinnamoyl chloride. The chloride was dissolved indichloromethane (10 ml) followed by addition of3-amino-4-(2-methylphenyl)-7,8-dihydrocyclopenta [g][1]benzopyran-2(6H)-one (582 mg) and N,N-dimethylaniline (0.25 ml). Themixture was then stirred at room temperature for 20 hours, after whichit was washed with water, dried (MgSO₄) and distilled to remove thesolvent. The residue was chromatographed on silica gel and eluted withbenzene-acetone (9:1) to give 3-(3,4-dimethoxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocyclopenta[g] 1benzopyran-2(6H)-one asoil. The oil was crystallized from ethanol-isopropyl ether (648 mg,67.4%). Recrystallization from acetone gave colorless needles, m.p.159°-160° C.

Elemental analysis, for C₃₀ H₂₆ NO₅ Calcd.: C, 74.98; H, 5.45; N, 2.91Found: C, 74.58; H, 5.89; N, 2.63

EXAMPLE 14

By the procedure of Example 13, there was synthesized3-(3,5-di-tert-butyl-4-hydroxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocyclopenta[g] [1]-benzopyran-2(6H)-one aspowder. Yield 25.0%

Elemental analysis, for C₃₆ H₃₉ NO₄ Calcd.: C, 78.66; H, 7.15; N, 2.55Found : C, 78.90; H, 7.01; N, 2.21

EXAMPLE 15

By the procedure of Example 13, there was synthesized3-(3,5-di-tert-butyl-4-hydroxyphenylacetylamino)-4-(2-methylphenyl)-7,8-dihydrocyclopenta -[g] [1]benzopyran-2(6H)-one.Yield 69.8%, m.p. 189°-190° C. (as recrystallized from ethanol-hexane)

Elemental analysis, for C₃₅ H₃₉ NO₄ Calcd.: C, 78.18; H, 7.31; N, 2.60Found : C, 77.99; H, 7.07; N, 2.68

EXAMPLE 16

To a solution ofN-(4-acetoxy-3,5-dimethoxyphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-yl]urea (400 mg) in tetrahydrofuran (4 ml) was added 10%methanolic hydrochloride (4 ml). The mixture was stirred at roomtemperature for 8 hours and the solvent was then distilled off. Theresidue was diluted with water and extracted with ethyl acetate. Theextract was washed with water, dried (MgSO₄) and distilled to remove thesolvent. To the residue was added ethanol to give crystals ofN-(4-hydroxy-3,5-dimethoxyphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g] [1]benzopyran-3-yl]urea (330 mg, 66.7%). Recrystallization fromethanol gave colorless needles, m.p. 176°-179° C.

Elemental analysis, for C₂₈ H₂₆ N₂ O₆.1/2H₂ O Calcd.: C, 67.87; H, 5.49;N, 5.65 Found: C, 68.16; H, 5.43; N, 5.33

EXAMPLE 17

By the procedure of Example 16, there was synthesizedN-(4-hydroxy-3,5-dimethylphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta-[g] [1]benzopyran-3-yl]urea. Yield 78.7%, m.p. 238°-239° C.

Elemental analysis, for C₂₈ H₂₆ N₂ O₄ Calcd.: C, 73.99; H, 5.77; N, 6.16Found: C, 74.01; H, 5.81; N, 5.93

EXAMPLE 18

To a solution of 3-(3,4-dimethoxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocylopenta [g] [1]benzopyran-2(6H)-one(400 mg) in dichloromethane (6 ml) was added borontribromidedichloromethane (1:2, 1 ml) dropwise with ice-cooling andstirring. The mixture was further stirred under ice-cooling for 1 hourand, then, added gradually to ethanol (5 ml) with ice-cooling. Themixture was diluted with water and extracted with ethyl acetate, theextract was washed with water and dried (MgSO₄), and the solvent wasdistilled off to give crystals of3-(3,4-dihydroxycinnamoylamino)-4-(2-methylphenyl)-7,8-dihydrocyclopenta[g] [1]benzopyran-2(6H)-one (361 mg, 95.8%). Recrystallization fromethanol gave light brown prisms, m.p. 295°-297° C.

Elemental analysis, for C₂₈ H₂₃ NO₅ Calcd.: C, 74.16; H, 5.11; N, 3.09Found : C, 73.95; It, 5.07; N, 2.97

EXAMPLE 19

By the procedure of Example 3, there was synthesizedN-(2,4-difluorophenyl)-N'-[1-methyl-4-(2-methylphenyl)-2-oxo-l,2,7,8-tetrahydro-6H-cyclopenta-[g]quinolin-3-yl]urea. Yield 78.9%, m.p. 230°-232° C. (asrecrystallized from methanol-chloroform)

Elemental analysis, for C₂₇ H₂₃ F₂ N₃ O₂ Calcd.: C, 70.58; H, 5.05; N,9.14 Found : C, 70.60; H, 5.02; N, 9.04

REFERENCE EXAMPLE 1

1) 2-Chlorobenzoyl chloride (11.8 g) was added dropwise to a stirredmixture of 5-aminoindan (9.0 g), potassium carbonate (9.3 g), ethylacetate (90 ml) and water (90 ml) under ice-cooling. The mixture wasfurther stirred under ice-cooling for one hour, at the end of which timethe organic layer was separated, washed with water, dried (MgSO₄) anddistilled to remove the solvent. The procedure gave crystals of5-2-chlorobenzoylamino)indan. The crystals were collected by filtrationand recrystallized from isopropyl ether to give colorless needles, m.p.144°-145° C.

2) A mixture of 5-(2-chlorobenzoylamino)indan (16 g), 2-chlorobenzoylchloride (15.5 g) and tin tetrachloride (10.2 ml) was heated at 130° C.for 30 minutes and, then, diluted with ethyl acetate (150 ml), followedby addition of 3N HCl (150 ml). The organic layer was separated andwashed with water, 2N NaOH and water in the order mentioned and thesolvent was distilled off. The residue was chromatographed on silica geland eluted with hexane-acetone (4:1) to give6-(2-chlorobenzoyl)-5-(2-chlorobenzoylamino)indan as oil (16.0 g,66.2%).

3) A mixture of 6-(2-chlorobenzoyl)-5-(2-chlorobenzoylamino)indan (16.0g) and 70% H₂ SO₄ (100 ml) was heated at 120° C. for 30 minutes and,then, poured in ice-water (300 ml). The solution was alkalinized withconcentrated aqueous ammonia and extracted with ethyl acetate. Theextract was washed with water and dried (MgSO₄) and the solvent wasdistilled off to give 5-amino-6-(2-chlorobenzoyl)indan as yellow oil(10.0 g, 94.3%). Recrystallization from hexane gave yellow prisms, m.p.90°-92°.

4) 1-Morpholino-2-nitroethene (3.93 g) was added to a mixture of5-amino-6-(2-chlorobenzoyl)indan (4.50 g), 6N HCl (15 ml) and acetone(45 ml) and the whole mixture was stirred at room temperature for onehour. To this reaction mixture was added water to give crystals of6-(2-chlorobenzoyl)-5-(2-nitroethenylamino)indan (5.40 g, 95.2%).Recrystallization from ethanol gave yellow needles, mp. 225°-226° C.

Elemental analysis, for C₁₈ H₁₅ ClN₂ O₃ Calcd.: C, 63.07; H, 4.41; N,8.17 Found: C, 62.74; H, 4.56; N, 7.80

5) 6-(2-Chlorobenzoyl)-5-(2-nitroethenylamino)indan (4.8 g) was added insmall portions to a solution of DBU (4.8 g) in benzene (50 ml) withheating at 90° C. The mixture was refluxed for 30 minutes and, then,washed with 2N HCl and water and dried (MgSO₄). The solvent was thendistilled off to give crystals of4-2-chlorophenyl)-7,8-dihydro-3-nitro-6H -cyclopenta[g]quinoline. Thecrystals were collected by filtration and washed with methanol (4.50 g,99.1%). Recrystallization from ethanol gave light brown prisms, mp.175°-176° C.

Elemental analysis, for C₁₈ H₁₃ ClN₂ O₂ Calcd.: C, 66.57; H, 4.03; N,8.63 Found : C, 66.29; H, 4.17; N, 8.33

6) To a mixture of4-(2-chlorophenyl)-7,8-dihydro-3-nitro-6H-cyclopenta[g]quinoline (4.50g), dioxane (45 ml) and concentrated hydrochloric acid (15 ml) was addedtin(II) chloride dihydrate (9.5 g) followed by stirring at roomtemperature for one hour. The reaction mixture was then diluted withwater, made strongly alkaline with 6N NaOH and extracted withchloroform. The extract was washed with water and dried (MgSO₄) and thesolvent was distilled off to give crystals of3-amino-4-(2-chlorophenyl)-7,8-dihydro-6H -cyclopenta[g]quinoline. Thecrystals were collected by filtration and washed with isopropyl ether(3.45 g, 83.3%). Recrystallization from ether gave colorless needles, mp179°-180° C.

Elemental analysis, for C₁₈ H₁₅ ClN₂ Calcd.: C, 73.34; H, 5.13; N, 9.50Found: C, 73.30; H, 5.32; , 9.20

REFERENCE EXAMPLE 2

The following compounds were synthesized in the same manner as ReferenceExample 1.

1) 5-(2-Methylbenzoylamino)indan: mp 160°-161° C.

2) 6-(2-Methylbenzoyl)-5-(2-methylbenzoylamino)indan: mp 124°-125° C.

3) 5-Amino-6-(2-methylbenzoyl)indan: mp 97°-98° C.

4) 6-(2-Methylbenzoyl)-5-(2-nitroethenylamino)indan: mp 205°-206° C.

5) 4-(2-Methylphenyl)-7,8-dihydro-3-nitro-6H-cyclo -penta[g]quinoline:mp 151°-152° C.

6) 3-Amino-4-(2-methylphenyl)-7,8-dihydro-6H-cyclo -penta(g)quinoline:mp 165°-166° C.

REFERENCE EXAMPLE 3

1) To an ice-cooled mixture of 5-hydroxyindan (13.4 g), triethylamine(14.0 ml) and dichloromethane (150 ml) was added 2-methylbenzoylchloride (15.4 ml) dropwise with constant stirring. The mixture wasfurther stirred under ice-cooling for one hour, after which it waswashed with water and dried (MgSO₄). The solvent was then distilled offto give 5-(2-methylbenzoyloxy)indan as oil in quantitative yield.

2) A mixture of 5-(2-methylbenzoyloxy)indan, obtained in 1) above, andaluminum chloride (16 g) was heated at 120° C. for 30 minutes. Aftercooling, the reaction mixture was added to a mixture of HCl (100 ml) andethyl acetate (100 ml) for extraction into ethyl acetate. The extractwas washed with water and dried (MgSO₄) and the solvent was distilledoff to give 5-hydroxy-6-(2-methylbenzoyl)indan as oil (24.6 g, 97.6%).Recrystallization from ethanol gave colorless prisms, mp 61°-62° C.

3) A mixture of 5-hydroxy-6-(2-methylbenzoyl)indan (10.08 g), diethylmalonate (12.8 g) and DBU (0.6 ml) was heated at 180° C. for 6 hours.After cooling, the reaction mixture was chromatographed on silica geland eluted with hexane-ethyl acetate (5:1). The solvent was thendistilled off to recover ethyl4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][-1]benzopyran-3-carboxylateas oil, which was then crystallized from ethanol (7.08 g, 50.9%).Recrystallization from ethanol gave colorless prisms, mp 113°-114° C.

Elemental analysis, for C₂₂ H₂₀ O₄ Calcd.: C, 75.84; H, 5.79 Found: C,75.70; H, 5.91

4) A mixture of ethyl 4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylate (5.0 g),concentrated hydrochloric acid (13 ml) and acetic acid (25 ml) wasrefluxed for 12 hours. To this reaction mixture was added water,whereupon 4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylic acid was obtained as crystals (4.5 g,97.8%). Recrystallization from acetone-hexane gave colorless prisms, mp213°-214° C.

Elemental analysis, for C₂ H₁₆ O₄ Calcd.: C, 74. 99; H, 5.03 Found : C,74. 85; H, 5.24

5) To a solution of 4-(2-methylphenyl)-2-oxo-2,6,7,8tetrahydrocyclopenta[g][1]benzopyran-3-carboxylic acid (2.5 g) and diphenyl phosphoryl azide(DPPA, 2.58 g) in tert-butanol (25 ml) was added triethylamine (1.1 ml)dropwise and the mixture was stirred at room temperature for 30 minutesand, then, refluxed for 4 hours. The solvent was distilled off and theresidue was diluted with water and extracted with ethyl acetate. Theextract was washed with water, dried (MgSO₄) and distilled to remove thesolvent, whereby3-tert-butyloxycarbonylamino-4-(2-methylphenyl)-7,8-dihydro-6H-cyclopenta[g][1]benzopyran-2-one was obtained as oil. The oil was crystallized fromhexane (2.95 g, 96.7%). Recrystallization from ethanol-hexane gavecolorless prisms, m.p. 154°-155° C.

Elemental analysis, for C₂₄ H₂₅ NO₄ Calcd.: C, 73.6 4; H, 6.44; N, 3.58Found : C, 73.91; I{, 6.52; N, 3.60

6) To a solution of 3-tert-butyloxycarbonylamino-4-(2methylphenyl)-7,8-dihydro-6H-cyclopenta [g] [1 ]benzopyran-2-one (2.05 g) indichloromethane (20 ml) was added trifluoroacetic acid (10 ml) dropwisewith ice-cooling. The mixture was stirred under ice-cooling for 1 hour,after which the solvent was distilled off. The residue was diluted withwater, neutralized with saturated aqueous solution of NaHCO₃ andextracted with chloroform. The extract was washed with water and dried(MgSO₄) and the solvent was distilled off to give crystals of3-amino-4-(2-methylphenyl)-7,8-dihydro-6H-cyclopenta[g][1]-benzopyran-2-one (1.5 g, 98.4%). Recrystallization fromethanol-dichloromethane gave colorless prisms, m.p. 275°-276° C.

Elemental analysis, for C₁₉ H₁₇ NO₂ Calcd.: C, 78.33; H, 5.88; N, 4.81Found : C, 78.15; H, 5.85; N, 4.58

REFERENCE EXAMPLE 4

1) To a solution of 1-bromo-5,6,7,8-tetrahydro-2-naphthol (6.81 g) andtriethylamine (4.2 ml) in dichloromethane (60 ml) was added2-methylbenzoyl chloride (4.62 g) dropwise with ice-cooling. The mixturewas stirred under ice cooling for 1 hour, after which it was washed withwater and dried (MgSO₄). The solvent was then distilled off to give1-bromo-2-(2-methylbenzoyloxy)-5,6,7,8-tetrahydronaphthalene as oil inquantitative yield.

2) A mixture of the 1-bromo-2-(2-methylbenzoyloxy)-5,6,7,8-tetrahydronaphthalene obtained in 1) and aluminum chloride (4.8g) was heated at 120° C. for 1 hour. After cooling, the mixture wasadded to 2N HCl (50 ml)-ethyl acetate (50 ml). The ethyl acetate layerwas taken, washed with water and dried (MgSO₄) and the solvent wasdistilled off, leaving an oil behind. To this oil was added ethanol togive crystals of 1-bromo-3-(2-methylbenzoyl)-5,6,7,8-tetrahydro-2-naphthol (4.0 g, 40.0%).Recrystallization from ethanol gave yellow prisms, m.p. 151°-153° C.

Elemental analysis, for C₁₈ H₁₇ BrO₂ Calcd.: C, 62.62; H, 4.96 Found: C,62.52; H, 5.03

3) A mixture of1-bromo-3-(2-methylbenzoyl)-5,6,7,8-tetrahydro-2-naphthol (3.33 g),sodium acetate (0.82 g), 5% palladium-on-carbon (50% hydrate, 1.0 g) andmethanol (10 ml) was subjected to catalytic reduction. After thetheoretical amount of hydrogen had been absorbed, the catalyst wasfiltered off. The solvent was then distilled off and the residue wasdiluted with water and extracted with ethyl acetate. The extract waswashed with water and dried (MgSO₄) and the solvent was distilled off togive 3-(2-methylbenzoyl)-5,6,7,8-tetrahydro-2-naphthol as an oil (2.45g, 96.5%).

4) A mixture of the 3-(2-methylbenzoyl)-5,6,7,8-tetrahydro -2-naphtholobtained in 3) (2.45 g), diethyl malonate (3.1 g) and DBU (0.14 ml) washeated at 170°-180° C. with stirring for 7 hours. After cooling, thereaction mixture was chromatographed on silica gel and eluted withhexane-ethyl acetate (85:15) to give ethyl4-(2-methylphenyl)-2-oxo-6,7,8,9-tetrahydro-2H-naphtho[2,3-b]pyran-3-carboxylate as oil (3.0 g, 87.0%).

5) A mixture of the ethyl 4-(2-methylphenyl)-2-oxo-6,7,8,9-tetrahydro-2H-naphtho[2,3-b]pyran-3-carboxylate obtained in 4)(3.0 g), concentrated hydrochloric acid (10 ml) and acetic acid (10 ml)was refluxed for 17 hours. To this reaction mixture was added water togive crystals of4-(2-methylphenyl)-2-oxo-6,7,8,9-tetrahydro-2H-naphtho[2,3-b]pyran-3-carboxylicacid (2.35 g, 84.8%). Recrystallization from acetone-hexane gavecolorless prisms, m.p. 216°-217° C.

Elemental analysis, for C₂₁ H₁₈ O₄ Calcd.: C, 75.43; H, 5.43 Found : C,75.33; H, 5.53

REFERENCE EXAMPLE 5

1) A mixture of 5-amino-6-(2-methylbenzoyl)indan (5.02 g), diethylmalonate (6.4 g) and DBU (0.3 ml) was heated at 170°-180° C. for 1 hour.To this reaction mixture was added ethanol to give crystals of ethyl4-2-methylphenyl)-2-oxo-l,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (6.81 g, 98.1%). Recrystallizationfrom ethanol-chloroform gave colorless crystals, m.p. 296°-298° C.

Elemental analysis, for C₂₂ H₂₁ NO₃ Calcd.: C, 76.06; H, 6.09; N, 4.03Found : C, 76.11; It, 6.20; N, 4.18

2) To a mixture of ethyl 4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (3.0 g),potassium carbonate (1.43 g) and DMF (30 ml) was added methyl iodide(0.65 ml) dropwise. The mixture was stirred at room temperature for 10hours, after which water was added to the reaction mixture to givecrystals of ethyl1-methyl-4-(2-methylphenyl)-2-oxo-l,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (2.95 g, 94.6%). Recrystallization from ethylether-isopropyl ether gave colorless needles, m.p. 134°-135° C.

Elemental analysis, for C₂₃ H₂₃ NO₃ Calcd.: C, 76.43; H, 6.41; N, 3.88Found: C, 76.31; H, 6.60; N, 3.65

3) A mixture of ethyl1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate(2.0 g), potassium hydroxide (1.55 g) and 80% ethanol (20 ml) wasstirred at 80° C. for 20 minutes. The mixture was diluted with water andacidified with 2N NCl to give crystals of 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylic acid(1.85 g, 99.6%).

Recrystallization from acetone gave colorless prisms, m.p. 231°-232° C.

Elemental analysis, for C₂₁ H₁₉ NO₃ Calcd.: C, 75.66; H, 5.74; N, 4.20Found: C, 75.78; H, 5.49; N, 4.00

REFERENCE EXAMPLE 6

1) The procedure of Reference Example 5°-1) was followed to synthesizeethyl 4-(2-chlorophenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate. Yield58.8%, mp. 285°-287° C. (recrystallized from ethanol-chloroform).

2) A mixture of the ethyl 4-(2-chlorophenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate obtainedin 1) (3.0 g) and phosphorus oxychloride (15 ml) was heated at 110° C.for 1 hour. The excess phosphorus oxychloride was distilled off and theresidue was poured in water, neutralized with saturated aqueous solutionof NaHCO₃ and extracted with ethyl acetate. The extract was washed withwater, dried (MgSO₄) and distilled to remove the solvent. The proceduregave crystals of ethyl2-chloro-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline-3-carboxylate(2.85 g, 90.5%). Recrystallization from ethanol gave colorless needles.

Elemental analysis, for C₂₁ H₁₇ Cl₂ NO₂ Calcd.: C, 65.20; H, 4.44; N,3.63 Found : C, 65.12; H, 4.35; N, 3.65

3) To a solution of ethyl 2-chloro-4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinoline-3-carboxylate (1.93 g) intetrahydrofuran-methanol (1:1, 15 ml) was added sodium methoxide (28%methanolic solution, 1.5 ml) dropwise. The mixture was stirred at roomtemperature for 3 hours, followed by addition of 2N NaOH (5 ml), and themixture was heated at 80° C. for 30 minutes. The reaction mixture wasdiluted with water and adjusted to pH 4 with 2N HC1, whereupon crystalsof 4-(2-chlorophenyl)-2-methoxy-6,7-dihydro-6H-cyclopenta[g]quinoline-3-carboxylic acid separated out (1.3 g, 73.4%).Recrystallization from methanolchloroform gave colorless needles, m.p.221°-222° C.

Elemental analysis, for C₂₀ H₁₆ ClNO₃ Calcd.: C, 67.90; H, 4.56; N, 3.86Found: C, 67.80; H, 4.31; N, 3.93

REFERENCE EXAMPLE 7

1) To a mixture of 5-methoxyindan-6-carboxylic acid (3.84 g), DMF (0.1ml) and tetrahydrofuran (50 ml) was added oxyalyl chloride (2.1 ml)dropwise. The mixture was stirred at room temperature for 1 hour, at theend of which time the solvent was distilled off to give5-methoxyindan-6-carboxylic acid chloride. This chloride was dissolvedin dichloromethane (50 ml) and after addition of 2,6-di-tert-butylphenol(4.12 g), tin tetrachloride (2.6 ml) was added dropwise withice-cooling. The mixture was stirred under ice-cooling for 30 minutesand, then, poured in diluted hydrochloric acid. The organic layer waswashed with water and dried (MgSO₄) and the solvent was distilled off.To the residue was added ethanol-hexane to give crystals of5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-methoxyindan (4.23 g, 55.7%).Recrystallization from ethanol gave colorless prisms, m.p. 154°-156° C.

Elemental analysis, for C₂₅ H₃₂ O₃ Calcd.: C, 78.91; H, 8.48 Found : C,78.97; It, 8.62

2) To a solution of5-(3,5-di-tert-butyl-4-hydroxybenzoyl)-6-methoxyindan (3.8 g) indichloromethane (30 ml) was added boron tribromide-dichloromethane (1:2,3 ml) dropwise with ice-cooling and stirring. The mixture was stirredunder ice-cooling for 15 minutes, after which ethanol (5 ml) was addeddropwise. The mixture was then washed with water and dried (MgSO₄) andthe solvent was distilled off. To the residue was added hexane to givecrystals of 5-(3,5-di -tert-butyl-4-hydroxybenzoyl)-6-hydroxyindan (3.06g, 83.6% ) . Recrystallization from ethanol gave light yellow prisms,m.p. 155°-156° C.

Elemental analysis, for C₂₄ H₃₀ O₃ Calcd.: C, 78.65; H, 8.25 Found : C,78.81; H, 8.20

3 ) A mixture of 5- (3,5-di-tert-butyl-4-hydroxybenzoyl)-6-hydroxyindan(2.8 g), diethyl malonate (3.6 g) and DBU (0.12 ml) was heated at160°-170° C. for 2 hours. After cooling, the resulting crystals werecollected by filtration and washed with ethanol to give ethyl4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g] [1]benzopyran-3-carboxylate (3.1 g, 87.8%). Recrystallization fromethanol gave colorless prisms, m.p. 208°-209° C.

Elemental analysis, for C₂₉ H₃₄ O₅ Calcd.: C, 75 .30; H, 7.41 Found : C,75 .19; H, 7.40

4) A mixture of ethyl 4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta [g][1]benzopyran-3-carboxylate (1.85 g), potassium hydroxide (1.12 g) and80% ethanol (12 ml) was stirred at room temperature for 3 hours. Thereaction mixture was then diluted with water, adjusted to pH4 with 6NHCl and extracted with ethyl acetate. The extract was washed with waterand dried (MgSO₄) and the solvent was distilled off to give crystals of4-3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylic acid. The crystals were collected byfiltration and washed with isopropyl ether (1.13 g, 64.9%). mp.256°-260° C.

(g) Effects of the Invention

The compound (I) or a pharmaceutically acceptable salt thereof accordingto the present invention has excellent ACAT inhibitory activity and isof value as a medicine for the prevention and treatment ofhypercholesterolemia and atherosclerosis or various associated diseases(viz. ischemic heart diseases such as myocardial infarction andcerebrovascular disorders such as cerebral infarction and cerebralapoplexy).

What we claim is:
 1. A heterocyclic compound of the general formula:##STR24## wherein ring A and ring B each mean a benzene ring which isunsubstituted or substituted by 1 to 4 substituents selected from agroup consisting of a halogen, C₁₋₆ alkyl optionally halogenated, C₁₋₆alkoxy optionally halogenated, C₁₋₆ alkylthio optionally halogenated,C₁₋₃ acyloxy, di-C₁₋₆ alkylamino and hydroxy; X means a group of theformula: ##STR25## wherein R² is hydrogen, an alkyl or an alkoxy; m is 0or 1, or the formula: ##STR26## wherein R³ is hydrogen or an alkyl; Ymeans a bond, --NH--, and C₁ or 2 alkylene group or --CH═CH--; R¹ is aC₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl orC₇₋₁₆ aralkyl group optionally substituted by 1 to 5 substituentsselected from a group consisting of a halogen, C₁₋₆ alkyl optionallyhalogenated, C₁₋₆ alkoxy optionally halogenated, C₁₋₆ alkylthio whichmay be halogenated, C₁₋₃ acyloxy, di-C₁₋₆ alkylamino and hydroxy; and nmeans a whole number of 3 through 6, or a pharmaceutically acceptablesalt thereof.
 2. A compound as claimed in claim 1, wherein the alkyl isa C₁₋₆ alkyl.
 3. A compound as claimed in claim 1, wherein the alkoxy isa C₁₋₆ alkoxy.
 4. A compound as claimed in claim 1, wherein the ring Ais a benzene ring substituted by 1 to 3 substituents selected from agroup consisting of halogen, C₁₋₆ alkyl and hydroxy; the ring B is abenzene ring; X is a group of the formula: ##STR27## wherein R² ishydrogen or a C₁₋₆ alkoxy, the formula: ##STR28## wherein R³ is a C₁₋₆alkyl; Y is --NH--, an C₁ or 2 alkylene group or --CH=CH--; R¹ is aphenyl group substituted by 1 to 3 substituents selected from a groupconsisting of a halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyloxy,. di-C₁₋₆alkylamino and hydroxy; and n is
 3. 5. A compound as claimed in claim 1,wherein the ring A is a benzene ring substituted by halogen or C₁₋₆alkyl; the ring B is a benzene ring; X is a group of the formula:--N=CH--; Y is --NH--; R¹ is ##STR29## and n is 3
 6. A compound asclaimed in claim 5, which isN-[4-(2-chlorophenyl)-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl]-N'-(2,4-difluorophenyl)urea.
 7. An acyl-CoA:cholesterolacyltransferase inhibitor composition which contains an effective amountof a heterocyclic compound of the general formula: ##STR30## whereinring A and ring B each means a benzene ring which is unsubstituted orsubstituted by 1 to 4 substituents selected from a group consisting of ahalogen, C₁₋₆ alkyl optionally halogenated, C₁₋₆ alkoxy optionallyhalogenated, C₁₋₆ alkylthio optionally halogenated, C₁₋₃ acyloxy,di-C₁₋₆ alkylamino and hydroxy, X means a group of the formula:##STR31## wherein R² is hydrogen, an alkyl or an alkoxy; m is 0 or 1, orthe formula: ##STR32## wherein R³ is hydrogen or an alkyl; Y means abond, --NH--, an C₁ or 2 alkylene or --CH=CH--; R¹ is a C₁₋₈ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl or C₇₋₁₆ aralkylgroup which may be substituted by 1 to 5 substituents selected from agroup consisting of a halogen, C₁₋₆ alkyl optionally halogenated, C₁₋₆alkoxy optionally halogenated, C₁₋₆ alkylthio optionally halogenated,C₁₋₃ acyloxy, di-C₁₋₆ alkylamino and hydroxy; and n means a whole numberof 3 through 6, or a pharmaceutically acceptable salt thereof,optionally together with a pharmaceutically acceptable carrier.
 8. Amethod for inhibiting acyl-CoA:cholesterol acyltransferase whichcomprises administrating an effective amount of a compound as claimed inclaim 1 optionally together with a pharmaceutically acceptable carrierto a mammal requiring such inhibition.